Scaffold Diversity for Enhanced Activity of Glycosylated Inhibitors of Fungal Adhesion

Candida albicans is one of the most prevalent fungal pathogens involved in

hospital acquired infections. It uses adhesins to bind to glycans at the cell surface of epithelial

cells and thus initiate infection. These interactions can be blocked by synthetic carbohydrates

(such as compound 1) that mimics the structure of cell surface glycans. Herein we report the

synthesis of a new series of divalent galactosides featuring aromatic (benzene, squaramides)

and aliphatic (norbornenes) central scaffolds, with the latter being the first examples of their

kind as small molecule anti-adhesion glycoconjugates. The evaluation of these compounds as

inhibitors of adhesion of C. albicans o exfoliated buccal epithelial cells (BECs) revealed that

galactosides 1 and 6, built on an aromatic core, were the most efficient inhibitors of adhesion,

displacing up to 36% and 48%, respectively, of yeast cells already attached to the BECs at

0.138 μM. Conformational analysis of compound 1 identified the preference for a folded

presentation in the lowest energy conformers. Remarkably, cis-endo-norbornene 21 performed

comparably to the benzene-core derivatives, highlighting the potential of norbornenes as a new

class of aliphatic scaffolds for the synthesis of anti-adhesion compounds.

Abstract